Abstract P5-06-07: Luminal-to-basal subtype conversion is governed by TP53-GATA3 mutational status and is targetable by MAPK inhibition in patients with breast cancer

Abstract Background: The molecular subtype largely governs therapeutic strategy in breast cancer patients, but the subtype is not static but frequently changes during treatment courses. The selective pressure on anti-tumor therapy is believed to drive lineage plasticity in luminal breast cancers, promoting a transition to basal-like phenotype and enhancing resistance against endocrine and targeted therapy. This study aims to elucidate the molecular mechanisms underlying luminal-to-basal (LB) subtype conversion through comprehensive genomic and molecular analyses. Methods: We utilized the prospective metastatic breast cancer database to identify patients with LB subtype conversion and luminal-to-luminal (LL) subtype maintenance in matched primary and secondary tumor tissues. Whole-exome sequencing (WES) and RNA-seq were performed on available tumors of the patients (exploratory cohort). We also validated genomic alterations in a separate cohort of patients who received next-generation sequencing (NGS) for clinical practice (validation cohort). Molecular factors associated with LB conversion were manipulated in MCF7 and T47D cell lines to further explore changes driving lineage plasticitiy, including chromatin accessibility studies using ATAC-seq. Results: Our analysis of metastatic breast cancer cohort with paired biopsy (n= 359) revealed overall 29.2% conversion rate of subtypes. LB conversion (from HR+HER2− to TNBC, 8.6%) was the most common subtype conversion and was associated with poorer survival compared to LL subtype maintenance. In the exploratory cohort, TP53 mutations were significantly more prevalent in patients undergoing LB conversion (64.3% vs. 15.4%), whereas GATA3 mutations appeared to be protective (0% vs. 23.1%). The validation NGS cohort (n=70) further confirmed the enrichment of TP53 mutation (85.7% vs. 23.2%) and the protective role of GATA3 (7.1% vs. 24.6%) in patients with LB conversion. The RNA-seq analysis indicated upregulation of KRAS-dependent signatures and decreased GATA3 expression in secondary tumors after LB conversion in TP53-mutant patients. TP53 depletion in MCF7 cells led to reduced ERα level and tamoxifen resistance, accompanied by increased accessibility in genes related to development regulation and AP-1 binding. Further combined TP53 and GATA3 depletion synergistically induced basal phenotype by activating the KRAS-MAPK pathway. MAPK inhibition restored luminal phenotype and tamoxifen sensitivity in luminal breast cancer against LB conversion induced by TP53 and GATA3 knockdown. MAPK inhibition was also effective in overcoming endocrine therapy resistance in tamoxifen- and palbociclib-resistant breast cancer cells exhibiting the LB conversion phenotype. Conclusion: Our findings establish TP53 mutations as a crucial predictor of LB subtype conversion in luminal breast cancers, with GATA3 mutations offering a protective effect. Combined TP53 and GATA3 loss synergistically promotes induction of basal phenotype through KRAS activation, and MAPK inhibition is a potential therapeutic strategy for luminal breast cancer patients with LB conversion. Citation Format: Min Hwan Kim, Won-Ji Ryu, Tae Yeong Kim, Yumi Hwang, Hyun-Yi Kim, Hyun Ju Han, Seul-Gi Kim, Gun Min Kim, Ja Seung Koo, Hyung Seok Park, Seung Il Kim, Joohyuk Sohn. Luminal-to-basal subtype conversion is governed by TP53-GATA3 mutational status and is targetable by MAPK inhibition in patients with breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P5-06-07.